A G protein signaling-biased agonist at the μ-opioid receptor reverses morphine tolerance while preventing morphine withdrawal

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It has been demonstrated that opioid agonists that preferentially act at μ-opioid receptors to activate G protein signaling over βarrestin2 recruitment produce antinociception with less respiratory suppression. However, most of the adverse effects associated with opioid therapeutics are realized after extended dosing. Therefore, we tested the onset of tolerance and dependence, and assessed for neurochemical changes associated with prolonged treatment with the biased agonist SR-17018. When chronically administered to mice, SR-17018 does not lead to hot plate antinociceptive tolerance, receptor desensitization in periaqueductal gray, nor a super-sensitization of adenylyl cyclase in the striatum, which are hallmarks of opioid neuronal adaptations that are seen with morphine. Interestingly, substitution with SR-17018 in morphine-tolerant mice restores morphine potency and efficacy, whereas the onset of opioid withdrawal is prevented. This is in contrast to buprenorphine, which can suppress withdrawal, but produces and maintains morphine antinociceptive tolerance. Biased agonists of this nature may therefore be useful for the treatment of opioid dependence while restoring opioid antinociceptive sensitivity.

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  1. 1.

    Pasternak GW. Mu opioid pharmacology: 40 years to the promised land. Adv Pharmacol 2018;82:261–91.

  2. 2.

    Smith JS, Lefkowitz RJ, Rajagopal S. Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 2018;17:243–60.

  3. 3.

    Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci 2004;27:107–44.

  4. 4.

    DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharm Exp Ther 2013;344:708–17.

  5. 5.

    Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, et al. Structure-based discovery of opioid analgesics with reduced side effects. Nature 2016;537:185–90.

  6. 6.

    Schmid CL, Kennedy NM, Ross NC, Lovell KM, Yue Z, Morgenweck J, et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 2017;171:1165–75 e13.

  7. 7.

    Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999;286:2495–8.

  8. 8.

    Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, Caron MG. Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 2000;408:720–3.

  9. 9.

    Raehal KM, Bohn LM. The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics. Neuropharmacology 2011;60:58–65.

  10. 10.

    Raehal KM, Schmid CL, Groer CE, Bohn LM. Functional selectivity at the mu-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharm Rev 2011;63:1001–19.

  11. 11.

    Bohn LM, Lefkowitz RJ, Caron MG. Differential mechanisms of morphine antinociceptive tolerance revealed in (beta)arrestin-2 knock-out mice. J Neurosci 2002;22:10494–500.

  12. 12.

    Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharm Exp Ther. 2005;314:1195–201.

  13. 13.

    Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N. APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the micro-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy. J Pain Res 2019;12:927–43.

  14. 14.

    Schulteis G, Markou A, Gold LH, Stinus L, Koob GF. Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis. J Pharm Exp Ther 1994;271:1391–8.

  15. 15.

    Handal M, Grung M, Skurtveit S, Ripel A, Morland J. Pharmacokinetic differences of morphine and morphine-glucuronides are reflected in locomotor activity. Pharm Biochem Behav 2002;73:883–92.

  16. 16.

    Gowing L, Ali R, White JM, Mbewe D. Buprenorphine for managing opioid withdrawal. Cochrane Database Syst Rev 2017;2:CD002025.

  17. 17.

    Smith HS, Peppin JF. Toward a systematic approach to opioid rotation. J Pain Res 2014;7:589–608.

  18. 18.

    Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 2006;144:127–34.

  19. 19.

    Haber PS, Elsayed M, Espinoza D, Lintzeris N, Veillard AS, Hallinan R. Constipation and other common symptoms reported by women and men in methadone and buprenorphine maintenance treatment. Drug Alcohol Depend 2017;181:132–39.

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Morphine was provided by the NIDA Drug Supply Program. We thank Ms. Nina McFague for additional assistance in blinded dosing and observations in the behavioral studies.

Author information

TWG designed, performed, and analyzed the behavioral studies, and contributed to writing and editing. CLS designed, performed, and analyzed behavioral studies, and pilot brain signaling assays. ELS designed, performed, and analyzed biochemical studies in brain regions, and contributed to editing. FP and AAC blinding, drug preparation, surgeries, dosing, and scoring of the behavioral assays. J-HH performed cAMP studies in striatum, and editing. NMK performed synthesis of SR compounds, data preparation, and editing. MDC performed pharmacokinetic studies and analysis. TDB carried out chemical design and synthesis, funding, and contributed to writing and editing. LMB performed experimental design for cellular and PK, and behavioral studies, analysis, funding, and writing of the manuscript.

Correspondence to Laura M. Bohn.

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